Combination/association of adapalene and benzoyl peroxide for treating acne lesions

ABSTRACT

Acne lesions, whether of inflammatory and/or non-inflammatory type, are simultaneously or sequentially treated and their number reduced, via daily topical regimen, with the combination or association of adapalene or pharmaceutically acceptable salt thereof and benzoyl peroxide (BPO).

CROSS-REFERENCE TO PRIORITY/PROVISIONAL APPLICATIONS

This application claims priority under 35 U.S.C. §119 of FR 06/52968,filed Jul. 13, 2006, and of U.S. Provisional Application No. 60/833,491,filed Jul. 27, 2006, each hereby expressly incorporated by reference andeach assigned to the assignee hereof.

BACKGROUND OF THE INVENTION

1. Technical Field of the Invention

The present invention relates to the combined or associatedadministration of adapalene and of benzoyl peroxide for reducing thenumber of acne lesions.

2. Description of Background and/or Related and/or Prior Art

6-[3-(1-Adamantyl)-4-methoxyphenyl]-2-naphthoic acid (referred tohereinbelow as adapalene) is a naphthoic acid derivative with retinoidand anti-inflammatory properties. This molecule was the subject ofdevelopment for the topical treatment of common acne and of dermatosessensitive to retinoids.

Adapalene is marketed under the trademark Differin® at a weightconcentration of 0.1%, in the form of an “alcoholic lotion” solution, anaqueous gel and a cream. These compositions are useful for treatingacne. FR-2,837,101 describes adapalene compositions at a weightconcentration of 0.3%, for treating acne.

WO 03/055 472 moreover describes stable pharmaceutical compositionscomprising adapalene and benzoyl peroxide (BPO).

An article by Korkut and Piskin, J. Dermatology, 2005, 32: 169-173,reports the results of a study comparing a treatment combiningapplication of adapalene in the evening and application of BPO in themorning, relative to an application of each of the active principlesalone. The authors do not observe any superiority of the combinedtreatment over a period of 11 weeks of treatment.

SUMMARY OF THE INVENTION

It has now surprisingly been demonstrated that a therapeutic associationor combination of adapalene and BPO can produce a degree of success inreducing the number of acne lesions and an improvement in the clinicalcondition of patients that is markedly superior to a treatment based onadapalene alone or on BPO alone, while at the same time maintaining thesame skin tolerance.

The recommended treatment may take the form of a pharmaceuticalcomposition combining adapalene and BPO, or a concomitant application oftwo pharmaceutical compositions, one comprising adapalene and the othercomprising BPO.

The present invention thus features formulation of adapalene or apharmaceutically acceptable salt thereof for the preparation of apharmaceutical composition, especially at set doses, suited to beadministered in combination or in association with benzoyl peroxide(BPO), for the treatment of acne lesions, especially to reduce thenumber of acne lesions and to improve the clinical condition ofpatients.

Preferably, the acne lesions are of inflammatory and/or non-inflammatorytype.

Acne is initially characterized by keratinization disorders, which aresometimes invisible to the naked eye. Visible acne lesions then develop,while the size of the sebaceous glands and the production of sebumincrease.

The present invention specifically concerns acne lesions. The term “acnelesions” means non-inflammatory lesions (open and closed comedones) andinflammatory lesions (papules, pustules, nodules and cysts) caused byacne. Preferably, the inflammatory lesions are treated with theassociation or the combination according to the invention.

More preferably, the pharmaceutical composition is administered by dailycutaneous topical application. Stated differently, the invention relatesto the use of adapalene as an agent for potentiating the action of BPO.Reciprocally, BPO potentiates the action of adapalene.

The term “adapalene salts” means the salts formed with apharmaceutically acceptable base, especially mineral bases such assodium hydroxide, potassium hydroxide and ammonia or organic bases suchas lysine, arginine or N-methylglucamine. The term “adapalene salts”also means the salts formed with fatty amines such as dioctylamine andstearylamine.

The expression “combination of adapalene or salts thereof with benzoylperoxide” means a single composition comprising both adapalene or saltsthereof and benzoyl peroxide.

According to one preferred embodiment, the pharmaceutical composition isa fixed combination and comprises, in a pharmaceutically acceptablemedium, (i) at least one compound selected from adapalene andpharmaceutically acceptable salts thereof, and (ii) benzoyl peroxide(BPO). Preferably, the pharmaceutical composition is intended for asingle topical application per day.

The term “pharmaceutically acceptable medium” means a medium that iscompatible with the skin, mucous membranes and the integuments.

The term “fixed combination” should be understood as meaning acombination whose active principles are combined at fixed doses in thesame vehicle (single formula) that delivers them together to the pointof application. Preferably, the pharmaceutical composition in the formof a fixed combination is a gel; in this case, the two active principlesare dispersed and intimately mixed, during the manufacture, in the samevehicle, which delivers them together during the application of the gel.

In another embodiment of the invention, the pharmaceutical compositionis in the form of a composition A comprising adapalene, intended to beapplied concomitantly with a composition B comprising BPO. Preferably,composition A and composition B are presented in the form of a kit,preferably comprising two isolated compartments each containing one ofthe two pharmaceutical compositions A or B (dual pack) and allowingsimultaneous administration of the two compositions, or alternatively inthe form of a kit combining in the same presentation at least the twoproducts (compositions A and B) in two separate packages, preferably inthe form of tubes (co-packaging).

In this case, one skilled in the art will adapt the formula that is themost appropriate in terms of viscosity, additives, etc. to the selectedkit.

The expression “concomitant” application means that the compositions areto be applied to the skin simultaneously or one after the other, in anyorder, or in a sequential order (for example, in which the applicationof a pharmaceutical composition B comprising BPO precedes theapplication of the pharmaceutical composition A comprising adapalene),but within a time interval of less than 1 hour, preferably less than 30minutes, preferably less than 15 minutes, more preferably less than 5minutes or even less than 1 minute.

The invention thus also features a composition in kit form comprising atleast two components:

a first component comprising at least adapalene or a pharmaceuticallyacceptable salt thereof,

a second component comprising benzoyl peroxide, these two components tobe applied concomitantly to the skin, mucous membranes and/or theinteguments.

Compositions A and B are preferably suited for a single cutaneoustopical application per day.

The treatments have a variable duration, depending on the patient andthe severity of his acne. The treatment period may thus run from severalweeks to several months. A suitable treatment period or regimen is atleast two weeks, preferably from 1 to 6 months and more preferably aduration of about 3 months is preferable, the duration of the treatmentpossibly being prolonged, if necessary.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-4 are graphs showing the efficacy of adapalene+BPO according tothe invention versus adapalene alone, BPO alone and vehicle alone; and

FIG. 5 is a bar graph showing the effects on ear edema of a variety oftest compounds.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

All the pharmaceutical compositions according to the invention maycomprise from 0.01% to 2%, preferably from 0.05% to 0.5% andpreferentially from 0.1% to 0.3% of adapalene, and from 0.1% to 20% andpreferably from 0.5% to 10% of BPO, more preferably from 2% to 5% of BPOand preferentially 2.5% of BPO.

All the percentages are indicated by weight relative to the total weightof the composition.

The adapalene:BPO ratio is from 1:1 and 1:200 and, conversely, theBPO:adapalene ratio is from 1:1 and 1:200. Preferably, the adapalene:BPOratio is from 1:1 and 1:200 and the adapalene:BPO ratio is preferably1:25.

Preferably, the effect of the combination of the two active principlesis at least an additive effect and preferentially a potentiation orsynergistic effect. The terms “potentiation effect” and “synergisticeffect” mean a therapeutic effect (degree of success) greater than theeffect resulting from the addition of the effects obtained by each ofthe two active principles taken separately.

When they are combined in the same pharmaceutical composition, theadapalene and the BPO are present in the pharmaceutical composition insynergistic amounts, i.e., such that a synergistic or potentiationeffect on the acne lesions and on the clinical condition of the patientis observed. Preferably, the pharmaceutical composition comprises 0.1%of adapalene and 2.5% of BPO.

When compositions A and B are used separately, the adapalene and the BPOare, respectively, present in composition A and composition B insynergistic amounts, i.e., such that a synergistic or potentiationeffect on the acne lesions and on the clinical condition of the patientis observed, especially when the compositions are applied in associationin equal amounts. Preferably, composition A comprises 0.1% of adapaleneand composition B comprises 2.5% of BPO.

In this regard, the examples to follow demonstrate that due to thesynergistic effect of adapalene and BPO, the invention provides greaterefficacy for the treatment of acne in general and of acne lesions inparticular and a quicker onset of action relative to monotherapies.

The pharmaceutical compositions according to the invention may be in theform of ointments, emulsions preferably in the form of creams, milks orpomades; powders, impregnated pads, solutions, gels, sprays, lotions orsuspensions. They may also be in the form of suspensions of microspheresor nanospheres or of lipid or polymer vesicles or of polymer patchesand/or of hydrogels allowing controlled release. These compositions maybe in anhydrous form, in aqueous form or in the form of an emulsion.

In one preferred embodiment of the invention, the pharmaceuticalcompositions are in the form of a gel, a cream or a solution referred toas a lotion.

Preferably, the pharmaceutical compositions combining adapalene and BPO,or the pharmaceutical compositions A and/or B, are gels.

The pharmaceutical compositions according to the invention may containinert additives or combinations of these additives, such as:

wetting agents;

texture enhancers;

preservatives such as para-hydroxybenzoic acid esters;

stabilizers;

humidity regulators;

pH regulators;

osmotic pressure modifiers;

emulsifiers;

UV-A and UV-B screening agents; and

antioxidants, such as α-tocopherol, butylhydroxyanisole orbutylhydroxytoluene, superoxide dismutase, ubiquinol, or certainmetal-chelating agents.

Needless to say, one skilled in this art will take care to select theoptional compound(s) to be added to these compositions such that theadvantageous properties intrinsically associated with the presentinvention are not, or are not substantially, adversely affected by theenvisaged addition.

According to one particular embodiment, the pharmaceutical composition Acomprising adapalene may be an aqueous gel especially containing one ormore ingredients selected from the carbomer 940 (BF Goodrich Carbopol980) and propylene glycol, or a cream especially containing one or moreingredients selected from perhydrosqualene, cyclomethicone, PEG-20methylglucose sesquistearate and methylglucose sesquistearate or an“alcoholic lotion” solution based on polyethylene glycol.

Useful pharmaceutical compositions, comprising adapalene and BPO, aremoreover described in WO 03/055 472. Examples of such compositionscomprise, besides the active principles adapalene and BPO:

from 5% to 25% of water;

from 0 to 10%, preferably from 0 to 2% and preferably less than 0.5% ofliquid wetting surfactant;

from 0 to 10% of pro-penetrating agent; and

an aqueous phase comprising a pH-independent gelling agent.

According to one preferred embodiment, the preferred pharmaceuticalcomposition, comprising adapalene and BPO, is an aqueous gel having thefollowing formulation:

2.5% of BPO;

0.1% of adapalene;

0.10% of disodium EDTA;

4.00% of glycerol;

4.00% of propylene glycol;

and also, preferably:

0.05% of sodium docusate;

0.20% of poloxamer 124;

4.00% of sodium acryloyldimethyltaurate copolymer and isohexadecane andpolysorbate 80;

NaOH, in an amount sufficient to obtain a pH of 5.

The acne targeted comprises all forms of acne, including common acne,comedones, polymorphs, nodulocystic acne, acne conglobata, and secondaryacne such as solar, medicational or occupational acne. The acne may inparticular be of mild to severe intensity and preferably of mild tomoderate intensity. The compositions according to the invention may beadministered as a firstline treatment, and also after failure of otherspecific treatments including the administration of adapalene and/or ofBPO according to the conditions described by Korkut et al.

The association or combination of adapalene and of BPO makes it possibleto reduce not only the number of inflammatory acne lesions but also thenon-inflammatory acne lesions and to observe an improvement in thepatient's clinical condition. A potentiation or synergistic effect isobserved. This potentiation effect described in the example below isshown in the reduced number of lesions and in the percentage of curedpatients (clear) and almost cured patients (almost clear) by the size ofthe superiority of the combination at fixed doses of adapalene and ofBPO, relative to the active substances taken individually at the samedoses as the combination.

Moreover, the results of the potentiation effect of the combination ofadapalene and BPO presented in the example are statistically differentfrom the results obtained for the active substances taken individually.

The combination or association of adapalene and of BPO is thusparticularly useful for reducing the number of inflammatory and/ornon-inflammatory acne lesions. Preferably, the reduction is at leastabout 40%, preferably at least about 50% and more preferably thereduction is at least about 60%. Similarly, it is demonstrated in theexample that the reduction of the total lesions is from about 35% to 80%and preferably from about 50% to 70%.

According to another aspect, the invention also features apharmaceutical assembly (product) comprising:

i) a container delimiting at least one compartment, the said containerbeing closed by means of a closing member; and

ii) a pharmaceutical composition comprising adapalene or apharmaceutically acceptable salt thereof and benzoyl peroxide asdescribed above, and placed inside the said compartment.

The container may be in any suitable form. It may especially be in theform of a bottle, a tube, a jar, a case, a can, a sachet or a box.

Preferably, the container comprises two compartments, and each of thesecompartments comprises either composition A or composition B.

The closing member may be in the form of a removable stopper, a lid, acover, a tear-off strip or a cap, especially of the type comprising abody fixed to the container and a cap articulated on the body. It mayalso be in the form of a member ensuring the selective closure of thecontainer, especially a pump, a valve or a clapper.

The closing member may be coupled to the container by screwing.Alternatively, the coupling from the closing member and the containermay take place other than by screwing, especially via a bayonetmechanism, by click-fastening, gripping, welding, bonding or magneticattraction. The term “click-fastening” in particular means any systeminvolving the passing of a rim or bead of material by elasticdeformation of a portion, especially of the closing member, followed byreturn to the elastically unstressed position of the said portion afterthe rim or bead has been passed.

The container may be at least partly made of thermoplastic material.Examples of thermoplastic materials that are representative includepolypropylene and polyethylene.

Alternatively, the container is made of a non-thermoplastic material,especially of glass or metal (or alloy).

The container may have rigid walls or deformable walls, especially inthe form of a tube or a tube bottle.

The container may comprise means for causing or facilitating thedistribution of the composition. By way of example, the container mayhave deformable walls so as to make the composition come out in responseto a positive pressure inside the container, this positive pressurebeing caused by elastic (or non-elastic) squeezing of the walls of thecontainer. Alternatively, especially when the product is in the form ofa stick, this stick may be driven by a piston mechanism. Still in thecase of a stick, especially of makeup product, the container maycomprise a mechanism, especially a wishbone mechanism, or a mechanismwith a threaded stem, or with a helical ramp, which is capable of movinga stick in the direction of the said opening. Such a mechanism isdescribed, for example, in FR-2,806,273 or in FR-2,775,566. Such amechanism for a liquid product is described in FR-2,727,609.

In order to further illustrate the present invention and the advantagesthereof, the following specific examples are given, it being understoodthat same are intended only as illustrative and in nowise limitative. Insaid examples to follow, all parts and percentages are given by weight,unless otherwise indicated.

EXAMPLES Example 1 Clinical Study Results

A clinical study for confirmation of efficacy was performed for atopical gel combining adapalene+benzoyl peroxide (BPO).

This gel has the following formulation (expressed as % weight/totalweight):

Adapalene 0.10% Benzoyl peroxide 2.50% Copolymer of acrylamide & sodium4.00% acryloyldimethyltaurate Sodium docusate 0.05% Disodium EDTA 0.10%Glycerol 4.00% Poloxamer 124 0.20% Propylene glycol 4.00% Purified waterqs 100%

Protocol:

The clinical study was a multi-centre, randomized, double-blind study inparallel groups, to evaluate the tolerance and the efficacy of the aboveformulation, in comparison with its own individual active substancesplaced at the same doses in gels of the same formula as that of thefixed combination (individual formulae referred to as “monads”) and incomparison with the gel vehicle (placebo formula): adapalene gel (0.1%),BPO gel (2.5%) and vehicle gel.

All the treatments were applied once a day for 12 weeks, to 517 patientssuffering from acne.

The main efficacy criteria were:

the degree of success, defined as the percentage of patients consideredas being “clear”, i.e., the patient has no more acne lesions (neithercomedones nor inflammatory lesions), reflecting an improvement in thepatient's clinical condition, or “almost clear” on the evaluation scale;

the reduction of the percentage of inflammatory and non-inflammatorylesions after 12 weeks of treatment.

Results:

The results are presented in the table that follows and in FIGS. 1-4.

Efficacy in week 12 ITT* Adapalene BPO 0.1% + Adapalene 2.5% Vehicle BPO2.5% 0.1% alone alone (gel) N = 149 N = 148 N = 149 N = 71 Degree ofsuccess (see 27.5% 15.5% 15.4% 9.9% FIG. 4) Progress of the lesions(median percentages) Number of inflammatory −62.8% −45.7% −43.6% −37.8%lesions (see FIG. 2) Number of non- −51.2% −33.3% −36.4% −37.5%inflammatory lesions (see FIG. 3) Total number of lesions −51.0% −35.4%−35.6% −31.0% (see FIG. 1) Progress of the lesions (as median absolutenumbers) Number of inflammatory −17 −13.0 −13.0 −11.0 lesions Number ofnon- −22.0 −17.0 −16.0 −14.0 inflammatory lesions Total number oflesions −40.0 −29.0 −27 −26.0ITT* (analysis of intention to treat): all the patients randomized in aclinical test because they come under the indication selected for thetreatment to be prescribed. The missing data are imputed by the lastobservation (LOCF method ** (Last Observation Carried Forward).

For the 4 main criteria of the study: degree of success and progress asa percentage of the three types of lesion, the fixed combination wasfound to be statistically superior to the two monads and to the vehicle.

When the effect of the gel used as vehicle (V) is subtracted from theeffect of the fixed combination (C), the net clinical benefit of thefixed combination (C-V) is numerically superior to the sum of the netclinical benefits of each of the individual substances after subtractionof the vehicle effect from the adapalene (A) and BPO (B) branches,respectively, according to the equation:(C−V)>(A−V)+(B−V).

These results systematically show a potentiation effect since the netbenefit is in favor of the gel combining adapalene+BPO, with results, interms of degree of success, that are superior to the addition ofadapalene and BPO (28% for the combination, as opposed to 16%, 15% and10% for adapalene, BPO and vehicle, respectively). In this case, theabove equation shows (28−10)>(16−10)+(15−10), i.e., 18>11, which istrue.

Similarly, the gel combining adapalene+BPO was numerically superior interms of efficacy in comparison with the individual active substancesand with the vehicle as regards the reduction in the number of all thelesions (reduction in the percentage of inflammatory andnon-inflammatory lesions).

A potentiation effect of adapalene and BPO together is thus noted, sincea 51% reduction in lesions is observed for the combination, as opposedto 35% for adapalene alone, 36% for BPO alone and 31% for the vehicle,which is expressed as a net benefit of efficacy with the above equationby (51−31)>(35−31)+(36−31), i.e., 20>9, which is accurate.

Example 2 Evaluation of the Anti-Inflammatory in Ear Edema Model onBalb/c Mice

The study was carried out with 45 (5 par groups) female 9 weeks agedBalb/c ByJlc mice.

The Edema was induced by a single application of 20 μl of TPA dissolvedin acetone at 0.01%.

The treatment was administrated by single topical application of testedcompounds dissolved in TPA at 0.01% (groups 3, 4, 5, 6 and 7) anddissolved in TPA 0.01%+BPO (groups 8, 9 and 10).

The treatments activity was measured by inflammation evaluation with earthickness at T+6 hours.

The results are presented in the following table and in FIG. 5.

Repeated Repeated Ear Edema Annova Annova Inhibition Testing vs Testingvs vs TPA alone TPA + BPO TPA (Dose (Dose Mean sem (%) Balanced)Balanced) Acetone TPA 0.01% 26.80 3.35 TPA 0.01% + 2.20 0.37 91.8 CD1530.01 (controle) TPA 0.01% + 22.40 2.23 16.4 0.042 BPO at 2.5% TPA0.01% + 20.40 2.62 23.9 BPO at 5% TPA 0.01% + 16.20 4.03 39.6 BPO at 10%TPA 0.01% + 23.40 2.01 12.7 Adapalene at 0.1% TPA 0.01% + 14.00 2.5147.8 Adapalene at 0.1% + BPO at 2.5% TPA 0.01% + 10.00 2.26 62.7 0.0015Adapalene at 0.1% + BPO at 5% TPA 0.01% + 11.00 3.03 59.0 Adapalene at0.1% + BPO at 10%

Conclusion:

After a single topical application of the positive control CD0153(0.01%) diluted in TPA solution, a decrease of 92% of the ear thicknesswas observed.

BPO at 2.5%, 5% and 10% has a slight anti-inflammatory effect, reducingthe TPA-induced ear edema respectively by 16%, 24% and 40%, with astatistically significant dose balanced effect (0.042).

Adapalene alone has a low anti-inflammatory effect, reducing theTPA-induced ear edema by 13%.

Variation of concentration of BPO was measured in combination withadapalene. Therefore, combinations of BPO at 2.5%, 5% and 10% withAdapalene at 0.1% reduce the TPA-induced ear edema respectively by 48%,63% and 59%. Combination treatment is statistically more efficient thanBPO alone (0.0015) even though the dose effect of the latest group isnon-significant regarding the TPA alone group (0.1089).

Adapalene at 0.1% increase the anti-inflammatory effect obtained withBPO whatever tested doses.

Lower doses of BPO will be used to attempt to show a dose related effectfor the association.

These results show a potential synergistic anti-inflammatory effect ofthe combination compared to the compounds singly applied.

Each patent, patent application, publication, text and literaturearticle/report cited or indicated herein is hereby expresslyincorporated by reference.

While the invention has been described in terms of various specific andpreferred embodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

What is claimed is:
 1. A regimen for the therapeutic treatment of acnelesions, the regimen comprising topically applying to the skin of asubject in need of said treatment, as active ingredients, 0.1% adapaleneor a pharmaceutically acceptable salt thereof and 2.5% benzoyl peroxide,combined at fixed doses in a single formula that delivers said activeingredients together synergistically to achieve, in a group of suchsubjects, a degree of success of at least about 20%, wherein theadapalene or pharmaceutically acceptable salt thereof and the benzoylperoxide are the only anti-acne active ingredients in said singleformula, wherein said single formula is applied once daily for a periodof 12 weeks.
 2. The regimen of claim 1, wherein the single formula is agel.
 3. A regimen for the therapeutic treatment of acne lesions, theregimen comprising topically applying to the skin of a subject in needof said treatment, as active ingredients, 0.1% adapalene or apharmaceutically acceptable salt thereof and 2.5% benzoyl peroxide,combined at fixed doses in a single formula that delivers said activeingredients together synergistically to reduce the number of total acnelesions by at least 40%, wherein the adapalene or pharmaceuticallyacceptable salt thereof and the benzoyl peroxide are the only anti-acneactive ingredients in said single formula, wherein said single formulais applied once daily for a period of 12 weeks.
 4. The regimen of claim3, wherein the single formula is a gel.
 5. A regimen for the therapeutictreatment of acne lesions, the regimen comprising topically applying tothe skin of a subject in need of said treatment, as active ingredients,0.1% adapalene or a pharmaceutically acceptable salt thereof and 2.5%benzoyl peroxide, combined at fixed doses in a single formula thatdelivers said active ingredients together synergistically to reduce thenumber of non-inflammatory acne lesions by at least 40%, wherein theadapalene or pharmaceutically acceptable salt thereof and the benzoylperoxide are the only anti-acne active ingredients in said singleformula, wherein said single formula is a gel which is applied oncedaily for a period of 12 weeks.
 6. A regimen for the therapeutictreatment of acne lesions, the regimen comprising topically applying tothe skin of a subject in need of said treatment, as active ingredients,0.1% adapalene or a pharmaceutically acceptable salt thereof and 2.5%benzoyl peroxide, combined at fixed doses in a single formula thatdelivers said active ingredients together synergistically to reduce thenumber of inflammatory acne lesions by at least 50%, wherein theadapalene or pharmaceutically acceptable salt thereof and the benzoylperoxide are the only anti-acne active ingredients in said singleformula, wherein said single formula is a gel which is applied oncedaily for a period of 12 weeks.
 7. A regimen for the therapeutictreatment of acne lesions, the regimen comprising topically applying tothe skin of a subject in need of such treatment, as active ingredients,0.1% adapalene or a pharmaceutically acceptable salt thereof and 2.5%benzoyl peroxide, combined at fixed doses in a single formula thatdelivers said active ingredients together synergistically to reduce thenumber of inflammatory lesions by at least 40%, wherein the adapalene orpharmaceutically acceptable salt thereof and the benzoyl peroxide arethe only anti-acne active ingredients in said single formula, whereinsaid single formula is applied once daily for a period of 12 weeks. 8.The regimen of claim 7, wherein the single formula is a gel.
 9. Aregimen for the therapeutic treatment of acne lesions, the regimencomprising topically applying to the skin of a subject in need of saidtreatment, as active ingredients, 0.1% adapalene or a pharmaceuticallyacceptable salt thereof and 2.5% benzoyl peroxide, combined at fixeddoses in a single formula that delivers said active ingredients togethersynergistically to reduce the number of total acne lesions by at least40%, to reduce the number of non-inflammatory acne lesions by at least40%, to reduce the number of inflammatory acne lesions by at least 40%and to achieve in a group of such subjects, a degree of success of atleast about 20%, wherein the adapalene or pharmaceutically acceptablesalt thereof and the benzoyl peroxide are the only anti-acne activeingredients in said single formula, wherein said single formula isapplied once daily for a period of 12 weeks.
 10. The regimen of claim 9,wherein the single formula is a gel.
 11. A regimen for providing earlyonset of action in the therapeutic treatment of acne lesions, theregimen comprising topically applying to the skin of a subject in needof said treatment, as active ingredients, adapalene or apharmaceutically acceptable salt thereof and benzoyl peroxide, combinedat fixed doses of 0.1% adapalene and 2.5% benzoyl peroxide in a singleformula that delivers said active ingredients together, wherein theadapalene or pharmaceutically acceptable salt thereof and the benzoylperoxide are the only anti-acne active ingredients in said singleformula, wherein said single formula is applied once daily for a periodof 12 weeks, and wherein the net clinical benefit, expressed as at leastone of success rate and reduction in total lesion counts in a group ofsuch subjects, at least one of week 1, week 2 and week 4, is numericallysuperior to the sum of the net clinical benefits achieved by 0.1%adapalene alone and 2.5% benzoyl peroxide alone at least one of thecorresponding time points.
 12. The regimen of claim 10, wherein thesingle formula is a gel.